Histamines are implicated in a number of medical conditions, including inflammation, asthma, allergy, atopic dermatitis, stroke, myocardial infection, migraine, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and psoriasis. Histamines regulate the intensity and duration of immune responses and are involved in cell-to-cell communication. Histamines are also involved in leukocyte migration and bronchovasoconstriction. As established by radioligand binding, physiological assays, and molecular cloning, different types of receptors for histamines exist. Furthermore, specific histamine receptor subtypes are involved in specific medical conditions such that drugs with subtype selectivity can be utilized to target individual medical conditions.
At present there are four known human histamine receptors, H1, H2, H3 and H4, all of which are G-protein coupled molecules. Although the existence of histamine receptors had been established pharmacologically for decades, the H1 and H2 receptors were cloned only in 1991 (Yamashita et al. 1991 Proc. Natl. Acad. Sci. USA 88:11515; Gantz et al. 1991 Proc. Natl. Acad. Sci. USA 88:429), and the H3 receptor and the H4 receptor were not cloned until more recently [Lovenberg et al. 1999 J. Mol. Pharmacol. 55:1101; Oda et al. 2000 J. Biol. Chem. 275:36781; Zhu et al. 2001 Mol. Pharmacol. 59:434; Liu et al. 2001 Mol. Pharmacol. 59:420; Morse et al. J. Pharm. Exp. Ther. 296:1058 as well as U.S. Pat. No. 6,204,017 and WO 01/25432 A2 (PCT/US00/27481); WO 01/46414 A1 (PCT/JP00/09038); and Nguyen et al. 2001 Mol. Pharmacol. 59:427]. A review describing some of the important similarities and differences of these receptors can be found in Hough, L. (Mol. Pharmacol. 2001 59:415). Recent molecular studies have shown that a single form of the H3 gene can give rise to multiple mRNA isoforms in rat (Drutel et al. 2001 Mol. Pharmacol. 59:1) and in guinea pig (Tardival-Lacombe et al. 2000 Neuroreport 11:755). In humans, six splice variants of the H3 receptor were recently reported in thalamus (Coge et al. Biochem. J. 2001 355:279). These variants were found to be coexpressed in human brain, but their relative distribution varied in a region-specific manner. The variants displayed deletions in either the putative second transmembrane domain or in the third intracellular loop.
The recently described H4 receptor is a 390 amino acid, 7 transmembrane G protein-coupled receptor. Two sequences with minor differences have been reported for the H4 receptor. (Oda et al. 2000; Morse et al. 2001; Liu et al. 2001; Nguyen et al. 2001; and Zhu et al. 2001). Like H3 receptor, H4 receptor seems to couple to Gi/o, thereby inhibiting forskolin-activated cAMP formation (Zhu et al. 2001). Evidence for plasma membrane localization and agonist-stimulated internalization of the H4 receptor has been reported (Nguyen et al. 2001). However, unlike the nearly exclusive brain localization of the H3 receptor, the H4 receptor appears to be localized primarily in the bone marrow and leukocytes (especially eosinophils and neutrophils), with moderate levels of H4 in the spleen and small intestine and possibly in Mast cells. H4 receptor seems to be absent from the central nervous system. The tissue distribution of the H4 receptor suggests a role in immune system related functions, however, the precise biological role for the H4 receptor has not yet been defined. The identification of H4-selective drugs (ligands) will help to elucidate the role of this newly discovered receptor and may lead to new pharmacotherapies.
In view of the important role that histamines play in many physiological processes and medical conditions, there is a need for materials and methods, including novel histamine receptors, useful for the identification of agonists, inverse agonists and antagonists selective for specific types of histamine receptors.